PCT Application PCT/US14/30071, filed Mar. 15, 2014, the entire contents of which is incorporated by reference in its entirety, provided novel heteroaryl non-peptidic compounds capable of modulating the Mas receptor of the Renin-Angiotensin System (also referred to herein as “RAS”), and capable of mimicking, in part or in entirety, the in vitro and in vivo activities of the endogenous Mas receptor heptapeptide ligand Asp-Arg-Val-Tyr-Ile-His-Pro, known as Angiotensin 1-7, (also referred to herein as “A(1-7)”). The present invention describes the use of these compounds for the treatment of illnesses, diseases, disorders, and conditions that cause a decrease in muscle strength (also referred to herein as musculoskeletal diseases, and as muscle dysfunction and muscle-wasting diseases).
The primary function of muscle tissue in the body is to provide a source of power. Muscle can be divided into three types: skeletal muscle, cardiac muscle, and smooth muscle. Skeletal muscle is muscle tissue capable of generating force and transferring that force to the skeleton enables breathing, movement, and posture maintenance. Cardiac muscle is muscle of the heart. Smooth muscle is muscle tissue of the arterial and bowel walls. The methods and compositions of the present invention apply primarily to skeletal muscle and, with the published efficacy of A(1-7) in pre-clinical models of cardiac dysfunction, cardiac muscle, but may additionally positively affect smooth muscles. “Skeletal muscle” and “skeletal muscles” are defined as muscles with interactions with bones, tendons, and joints.
A large number of musculoskeletal diseases have been shown to lead to a decrease in muscle strength. These include, but are not limited to, inherited or recessive myopathies (such as muscular dystrophies), muscle-wasting diseases (such as cachexia that may be the result from underlying illnesses such as acquired immunodeficiency diseases [AIDS], rheumatoid arthritis, cancer, chronic obstructive pulmonary disease [COPD], and cirrhosis), conditions of muscle atrophy or attenuation (such as sarcopenia that may be the result of aging), protracted disuse (such as paralysis, coma, extended bed rest, and ICU stay), weakness induced by surgery (such as joint replacement surgery), drug-induced myopathy and rhabdomyolysis. Muscle pathology of these diseases and conditions are mediated, in part or in whole, by a combination of immune, inflammatory, and fibrotic responses. Agents capable of blocking these responses and/or stimulating regeneration of the damaged tissue would be capable of slowing or reversing disease progression in these disorders.
The heptapeptide A(1-7) has been shown to positively affect a number of disease states prevalent in patients suffering from diseases of attenuated muscle strength. A(1-7) has been shown to block cardiac fibrogenesis and remodeling resulting in a significant reduction interstitial myocardial fibrosis and myocyte hypertrophy [Iwata et al., 2005; Grobe et al., 2007]. Recent studies extrapolated these effects to skeletal muscle and showed in both the Dmdmdx and Sgcd−/− mouse models of muscular dystrophy (also referred to herein as “MD”), A(1-7) reduced fibrosis, oxidative stress, and improved measures of muscle strength which was tied in Dmdmdx mice to inhibition of TGF-β signaling [Acuña et al., 2014; Sabharwal et al., 2012]. Finally, A(1-7) has been shown to facilitate tissue regeneration and repair through stem cell activation [Jarajapu et al., 2013; Durik et al., 2012].
Elevated levels of angiotensin II (AngII) are seen in a number of conditions that are associated with muscle atrophy or cachexia and AngII has been shown experimentally to be an atrophic factor [Sukhanov et al., 2011; Brink et al., 2001]. In mice chronically infused with AngII via mini-pump, co-treatment with A(1-7) has been shown in to block the atrophic effects of AngII [Cisternas et al., 2015]. In this study, histologically A(1-7) co-treatment prevented a decrease in gastrocnemius muscle fiber diameter seen with AngII infusion alone. Also, performance on the weights test [Deacon 2013] was increased with AngII/A(1-7) co-treatment compared to AngII infusion alone. Additionally, in a mouse model of endotoxin-induced sepsis, following a single injection of lipopolysaccharide (LPS), LPS-injected mice infused with A(1-7) showed a similar decrease in skeletal muscle wasting (measured by muscle fiber diameter, weights test, and isolated tetanic-specific force) compared to LPS-injected mice infused with vehicle [Morales et al., 2015].
Despite these remarkable effects in these pre-clinical models, the A(1-7) peptide and related peptidic analogs are limited in their therapeutic potential due to their high cost of manufacture and limited methods of delivery, which are typically restricted to a parenteral route of administration (e.g., subcutaneous, intramuscular, and intravenous). Therefore, there is a need for small molecule non-peptidic compounds that act as effective Mas agonists and/or as A(1-7) mimics that can be used for the treatment of musculoskeletal diseases, including muscle-wasting and muscle dysfunction diseases.